Corticosteroid hormones are important in a wide variety of biological contexts and are widely used as therapeutic agents. The most prevalent uses of corticosteroids in the clinical environment include the treatment of asthma and the prenatal administration of corticosteroids to mothers expecting to deliver babies pre-term, in order to facilitate terminal lung morphogenesis. Despite the broad clinical utility of corticosteroids, not all patients respond to their therapeutic effects. Additionally, off target efects of corticosteroids include metabolic perturbations detrimental to patient health. Our recent research suggests that several novel mechanisms govern the activity and specificity of glucocorticoid (GC) signaling. Specifically, we have demonstrated that the vast minority of glucocorticoid receptor (GR) binding sites controls the majority of GC-induced gene expression. We provide evidence for a novel enhancer-cluster model of GR-induced gene activation. In this proposal we will test our core hypothesis that GR binding at sites that contain the canonical GR binding motif drive the primary transcription response to GCs and that AP1-tethered binding sites proximal to direct GR binding sites act secondarily to modulate the primary GC-induced transcription response. Ultimately understanding the molecular underpinnings that govern the activity of the GR will yield critical insights that could increase the clinical efficacy of GCs amng GC-nonresponsive patients and reduce the off target effects of corticosteroid therapies.